Down syndrome (DS), the most common genetic form of intellectual disability, is associated with significant functional heterogeneity. One of the largest barriers to understanding the basis for this heterogeneity is that existing data are heterogeneous and disaggregated; this severely limits both computational utility and clinical applicability. Through partnership with the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project and the Gabriella Miller Kids First Pediatric Research Program (Kids First), whole genome sequencing is being performed on over 6,000 samples for individuals with DS. The data from these samples will be used by a number of research projects towards understanding the genetic etiology underlying increased risk of congenital heart defects (CHD) and acute lymphoblastic leukemia (ALL) in children with Down Syndrome (DS). The Kids First Data Resource Center (DRC) will ensure genomic harmonization of these samples with other pediatric data generated by Kids First and other associated genomic datasets. The DRC also performs clinical data harmonization on a core set of fields across a wide variety of pediatric disease types, as there is recognition that increased standardization and computability increase the speed of scientific discovery. With the INCLUDE cohort, there is an opportunity to expand these capabilities towards improved harmonization of clinical instruments, especially in the domain of neurobehavior. Through this supplement, the assembled team will combine their expertise to overcome existing hurdles via two tasks: 1) Perform DS data standardization and 2) Extend DRC tooling and interfaces to support the Down Syndrome INCLUDE project. Together these two tasks will enable INCLUDE to expand DS cohorts and provide rapid ways to build new DS cohorts with common data elements, and to conduct high-risk/high reward genotype/phenotype studies to discover dysregulated genes on the trisomy 21 background followed by basic science studies. Moreover, this work could be expanded to other Kids First and trans-NIH initiatives in neurodevelopmental disorders.